The microbes that inhabit human bodies outnumber the human cells by an order of magnitude, and impact many aspects of health and disease including obesity, vaginosis, and Crohn's disease. Understanding this endogenous microbiota is emerging as a key extension of efforts to understand the human genome and the role of genetic variation on health and disease. The Human Microbiome Project (HMP) will characterize microbial communities in a large number of individual healthy humans using metagenomic sequencing. Consequently, new methods for interpreting sequence data to understand microbial community composition and dynamics are urgently needed. This project unites disciplines ranging from ecology to evolutionary biology to applied mathematics, to develop new methods for understanding which body habitats are more or less similar in terms of their microbial communities, by evaluating measures of microbial diversity and change, and creating needed new metrics of community composition. This will enable understanding of how clinically relevant parameters such as age, sex, or the pH of specific body habitats affect these communities, and of how the dynamics of change in microbial communities within an individual, in transmission between individuals, and in transmission between humans and the environment. This project is directly responsive to the Roadmap RFA for Development of New tools for Computational Analysis of Human Microbiome Project Data. The specific aims of this proposal are: Aim 1. Develop, characterize, and apply enriched descriptors of microbial community diversity. Aim 2. Develop methods for describing how human microbial communities vary over time and space. Aim 3. Develop new methods for tracing the flow of organisms among different communities. Some key aspects of the proposed work are: the development of new statistical methods for estimating microbial diversity within a body habitat; development of enriched methods for describing microbial community diversity; exhaustive validation of methods for comparing microbial communities through large-scale simulations and by using the largest available data sets that characterize microbial communities empirically; and the development of new methods for tracing the sources of the microbes that inhabit the human body using both marker genes and whole-metagenome data. Key outcomes include the ability to help determine the extent to which there is a core human microbiome, and how best to sample human microbial diversity. All methods developed will be made available under open source licenses and will be deposited with the HMP Data Analysis and Coordination Center (DACC). The investigators intend to work closely with other researchers involved in the HMP in order to ensure rapid progress. PUBLIC HEALTH RELEVANCE: Microbial communities associated with the human body play critical roles in human health and disease. This project will provide methods that help establish the nature and variability of microbial communities in healthy human individuals. Using these individuals as a baseline, this work will will pave the way for studies of a wide range of medical conditions that these communities affect by looking for abnormal communities associated with specific disease states, allowing the development of new diagnostics and therapeutic approaches.